Cancer and Evolution: Why Chemotherapy Fails

This section is dedicated to Robert Gatenby of the Moffitt Cancer Center, to whom I owe many of the ideas set out here.

Cancer evolves. Chemotherapies and other cancer treatments don’t fail because they’re ineffective. They fail because cancer has the unfortunate ability to evolve and adapt over time to whatever therapies we apply to it. Tumours evolve by much the same mechanisms which govern the evolution of species. Tumours are like a miniature ecosystem, and the cells composing it are subject to the processes of Darwinian natural selection, whereby the fittest cells, in terms of DNA replication, outcompete the less fit cells.

This can occur because the cells which make up a tumour are not all alike. They exist in different microenvironments with differing availability of oxygen and nutrients, and differing exposure to toxins such as chemotherapeutic agents. In short, they are exposed to different selective pressures depending on location, and adapt accordingly.

A helpful analogy to explain why chemotherapy fails is what happens when antibiotics are applied to deal with infection. The antibiotic may help fight the infection as intended, but it may also wipe out the beneficial microbial populations in the gut. Once these beneficial colonies are eliminated, resistant pathogenic colonies which existed there all along (like C. difficile) may now proliferate unchecked, because the competition has been eliminated.

A similar process may occur in cancer therapy. In the absence of cytotoxic drugs, chemosensitive cells have a fitness advantage because they are not forced to spend any cellular resources on resistance strategies, and may channel all their resources into proliferation. However, when a new chemotherapeutic drug is introduced, the chemosensitive cells in a tumour lose their advantage, are killed off, and the tumour may shrink accordingly, down to the point at which only resistant cells remain. The resistant cells, though not proliferating as quickly as the chemosensitive strains, gain the selective advantage, and may then proliferate without competition, until some new drug is applied to which they have not developed resistance.

A foreknowledge and anticipation of cancer’s resistance mechanisms can be exploited to human advantage. Using a combination of drugs with very different modes of action, either simultaneously or sequentially, should increase the “cost of resistance” to the point that resistant cells will be expending so much of their resources on multiple resistance mechanisms, that little will be left over for proliferation (1).

Another concept borrowed from ecology and applied by Gatenby to cancer therapy, is the “evolutionary double bind” (2). A prey species is forced to evolve resistance or avoidance strategies in the face of predation. However, another predator species may exploit those very strategies that the prey species uses to avoid the first predator. Likewise, we could theoretically apply one chemotherapeutic agent, knowing in advance how the tumour is likely to adapt. Then, we could apply a second therapeutic agent which takes full advantage of the adaptation to the first agent. Another point to consider is that the tumour adapts only to the conditions present. It can eventually lose resistance following removal of a drug, and it has no ability to plan ahead and anticipate future anti-cancer strategies. It is like a game of chess, except the cancer-player has no ability to anticipate the opponent’s next move (3).

In summary, we need firstly to have a knowledge as complete as possible about how a tumour is likely adapt to each individual therapeutic agent we will be using.

We need to strategically use a variety of agents that work with each other in various combinations and sequences that catch the tumour in an evolutionary double bind.

And we need to maximize the “cost of resistance” by forcing the tumour to adopt radical adaptation strategies that will deplete the bulk of its resources. For this, we need to maximize our arsenal of different therapeutic strategies, with the widest possible variety of different mechanisms of action.

  1. Evolutionary dynamics in cancer therapy. Cunningham et al. 2011.
  2. Lessons from applied ecology: cancer control using an evolutionary double bind. Gatenby et al. 2009.
  3. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Gillies et al. 2012.